The treatment of hypertension in people with dementia

Introduction Current guidance on the treatment of high blood pressure provides the advice that co-pathology should be taken into account when treatment decisions are made, but does not specify the approach in people with dementia. A relationship between high blood pressure and dementia, all be it complex and variable over time, does exist, making dementia a relevant co-pathology in decisions around the treatment of hypertension. No trial evidence exists however to guide clinical decision making in this specific context and clinicians with theoretical concerns over adverse events or varying priorities may act differently while remaining within the scope of current guidance. To inform the design of potential future research examining the repercussions of different treatment approaches, the way high blood pressure is currently treated in people with dementia and the adverse events they experience need to be understood. Aims This thesis reports research which set out to describe the treatment of high blood pressure in people with dementia and the adverse events that this population experienced over a six month period. Methods (i) A systematic literature review of observational studies describing the treatment of hypertension in people with dementia was performed. (ii) A multicentre cohort study, the Hypertension IN Dementia (HIND) study, of 181 participants, recorded information on dependency in activities of daily living (ADLs), cognition, medication, diagnoses, and healthcare use. It provided a detailed description of the treatment of high blood pressure in the study population and the adverse events experienced over a 6 month period. Results Literature review: The prevalence of hypertension in people with dementia was 45% (range 36%-84%), of whom 73% (range 48%-85%) were taking at least one antihypertensive. 55% of people with dementia achieved target blood pressure in the one study that reported this. The review found no studies that specifically set out to describe the treatment of high blood pressure in people with dementia in the UK. Cohort study: 181 participants were recruited from general practices and via memory clinics. The rate of recruitment was low (8%) in the GP arm, resulting in potential selection bias. The study population were mildly cognitively impaired (median MMSE 23 (IQR 18-26)), 56% were dependent for at least one ADL, had a median of 5 (IQR 3-7) diagnoses and were treated with a median of 7 (5-9) medications. High blood pressure was treated in 87% (95% CI 82% - 92%) and target blood pressure was achieved in 57% (95% CI 49% - 64%) of those on treatment, no different from the general population (87% (95% CI 85% - 89%) treated and 52% (95% CI 49% - 55%) achieving target). ACEi/ARBs were the most frequently prescribed antihypertensive class (55%), followed by calcium channel blockers (33%), beta-blockers (30%) and diuretics (21%). Diuretics were less likely to be prescribed than in the general population (21% (95% CI 15%-26%) vs 34% (95% CI 31% - 37%)). During 6 months follow up the study population reported 475 GP appointments, 65 hospital admissions, 214 falls, 1 myocardial infarction, 6 strokes and 8 deaths. Heart failure, stroke, recurrent falls, falls with fractures, death and GP appointments were more common in the study population than in benchmark populations. Conclusion In conclusion in an area where clinicians were acting without a firm evidence base and where there were theoretical concerns around the potential side effects of antihypertensive use, clinicians treated hypertension in people with dementia much as they did in people without dementia. The same classes of antihypertensives were used to maintain blood pressure at a similar level to that achievable in the general population. Despite a potential selection bias that may have over recruited fitter and milder people with dementia than the overall population, the study population reported a higher level of cardiovascular events, recurrent falls, fractures and adverse symptomatology than those without dementia in benchmark populations. Although this finding could relate to reporting bias or a higher intrinsic cardiovascular risk it raises the possibility that the benefits of antihypertensive treatment are attenuated, while the risks are increased, in people with dementia with implications for the risk-benefit ratio in this population. Future specific research, using an approach that avoids selection bias, to explore the risk-benefit ratio of antihypertensive treatment in people with dementia is outlined and advice is provided to clinicians managing high blood pressure in people with dementia

Prescribing of direct oral anticoagulants and warfarin to older people with atrial fibrillation in UK general practice:a cohort study

BackgroundAnticoagulation for stroke prevention in atrial fibrillation (AF) has, historically, been under-used in older people. The aim of this study was to investigate prescribing of oral anticoagulants (OACs) for people aged ≥ 75 years in the UK before and after direct oral anticoagulants (DOACs) became available.MethodsA cohort of patients aged ≥ 75 years with a diagnosis of AF was derived from the Clinical Practice Research Datalink (CPRD) between January 1, 2003, and December 27, 2017. Patients were grouped as no OAC, incident OAC (OAC newly prescribed) or prevalent OAC (entered study on OAC). Incidence and point prevalence of OAC prescribing were calculated yearly. The risk of being prescribed an OAC if a co-morbidity was present was calculated; the risk difference (RD) was reported. Kaplan-Meier curves were used to explore persistence with anticoagulation. A Cox regression was used to model persistence with warfarin and DOACs over time.ResultsThe cohort comprised 165,596 patients (66,859 no OAC; 47,916 incident OAC; 50,821 prevalent OAC). Incidence of OAC prescribing increased from 111 per 1000 person-years in 2003 to 587 per 1000 person-years in 2017. Older patients (≥ 90 years) were 40% less likely to receive an OAC (RD -0.40, 95% CI -0.41 to -0.39) than younger individuals (75-84 years). The likelihood of being prescribed an OAC was lower with a history of dementia (RD -0.34, 95% CI -0.35 to -0.33), falls (RD -0.17, 95% CI -0.18 to -0.16), major bleeds (RD -0.17, 95% CI -0.19 to -0.15) and fractures (RD -0.13, 95% CI -0.14 to -0.12). Persistence with warfarin was higher than DOACs in the first year (0-1 year: HR 1.25, 95% CI 1.17-1.33), but this trend reversed by the third year of therapy (HR 0.75, 95% CI 0.63-0.89).ConclusionsOAC prescribing for older people with AF has increased; however, substantial disparities persist with age and co-morbidities. Whilst OACs should not be withheld solely due to the risk of falls, these results do not reflect this national guidance. Furthermore, the under-prescribing of OACs for patients with dementia or advancing age may be due to decisions around risk-benefit management.Trial registrationEUPAS29923 . First registered on: 27/06/2019

Use of oral anticoagulants in older people with atrial fibrillation in UK general practice : protocol for a cohort study using the Clinical Practice Research Datalink (CPRD) database

Introduction Warfarin has frequently been underused in older people for stroke prevention in atrial fibrillation (AF). Direct oral anticoagulants (DOACs) entered the UK market from 2008 and have been recommended as an alternative to warfarin. This study aimed to describe any changes in the prescribing of oral anticoagulants (OACs) to people aged ≥75 years in UK general practice before and after the introduction of DOACs, to examine differences in patient characteristics which may influence prescribers' decisions regarding anticoagulation, to evaluate the time people stay on OACs and switching between OACs. Methods and analysis A retrospective cohort study design will be used. Patients with a diagnosis of AF will be identified from the Clinical Practice Research Datalink (CPRD). The study period will run from 1 January 2003 to 27 December 2017. Patients enter the cohort at the latest date of the start of the study period, first AF diagnosis, 75th birthday or a year from when they started to contribute research standard data. Follow-up continues until they leave the practice, death, the date the practice stops contributing research standard data or the end of the study period (27 December 2017). Exposure to OACs will be defined as ≥1 prescription issued for an OAC of interest during the study period. Patients issued an OAC in the year preceding study entry will be defined as a 'prevalent users'. Patients starting on an OAC during the study period will be defined as a 'incident users'. Incidence and prevalence of OAC prescribing, patient demographics and characteristics will be described during three time periods: 2003-2007, 2008-2012 and 2013-2017. Persistence (defined as the time from initiation to discontinuation of medication) with and switching between different OACs will be described. Ethics and dissemination The protocol for this study was approved by the CPRD Independent Scientific Advisory Committee. The results will be disseminated in a peer-reviewed journal and at conferences. Trial registration number EUPAS29923

Transforming undergraduate education in geriatric medicine:an innovative curriculum at Bristol Medical School

The World Health Organization (WHO) advocates investment in high-quality undergraduate education in geriatric medicine as a means of meeting the future needs of the aging population. However, there is a lack of evidence for the optimal delivery of training in this area. Rigorous pedagogical research is required to determine the most effective way to equip tomorrow’s doctors with the skills and knowledge to care for older adults with complex health and social care needs. The transition between two undergraduate medical curricula meant that Bristol Medical School (BMS) was uniquely positioned to innovate and evaluate undergraduate education in geriatric medicine. This transition marked BMS’ departure from a ‘traditional’ curriculum to case-based learning. The outgoing curriculum included a 4-week unit in geriatrics, whilst the new programme includes an 18-week clerkship titled ‘Complex Medicine in Older People’ (CMOP). CMOP is a clinical clerkship with 18 cases at its core, covering the fundamental aspects of geriatric medicine. The core cases and clinical learning are enhanced with five expert lectures, six tutorials and three journal clubs. Reflective practice is modelled and promoted with Balint groups and a book club. Consolidative workplace-based assessments and clinical portfolio mirror those used in postgraduate training, preparing students for professional practice. CMOP is iteratively improved in real-time using staff and student feedback. This marked shift in mode and duration of teaching affords the opportunity to evaluate the impact of differing education in geriatrics, providing an evidence-based model for teaching on aging. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s41999-022-00690-w

New horizons: the management of hypertension in people with dementia

The optimal management of hypertension in people with dementia is uncertain. This review explores if people with dementia experience greater adverse effects from antihypertensive medications, if cognitive function is protected or worsened by controlling blood pressure (BP) and if there are subgroups of people with dementia for whom antihypertensive therapy is more likely to be harmful. Robust evidence is scant, trials of antihypertensive medications have generally excluded those with dementia. Observational data show changes in risk association over the life course, with high BP being a risk factor for cognitive decline in mid-life, while low BP is predictive in later life. It is therefore possible that excessive BP lowering in older people with dementia might harm cognition. From the existing literature, there is no direct evidence of benefit or harm from treating hypertension in people with dementia. So what practical steps can the clinician take? Assess capacity, establish patient preferences when making treatment decisions, use ambulatory monitoring to thoroughly assess BP, individualise and consider deprescribing where side effects (e.g. hypotension) outweigh the benefits. Future research might include pragmatic randomised trials of targeted deprescribing, which include patient-centred outcome measures to help support decision-making and studies to address mechanistic uncertainties

Anticholinergic drug burden tools/scales and adverse outcomes in different clinical settings: a systematic review of reviews

Background: Cumulative anticholinergic exposure (anticholinergic burden) has been linked to a number of adverse outcomes. To conduct research in this area, an agreed approach to describing anticholinergic burden is needed. Objective: This review set out to identify anticholinergic burden scales, to describe their rationale, the settings in which they have been used and the outcomes associated with them. Methods: A search was performed using the Healthcare Databases Advanced Search of MEDLINE, EMBASE, Cochrane, CINAHL and PsycINFO from inception to October 2016 to identify systematic reviews describing anticholinergic burden scales or tools. Abstracts and titles were reviewed to determine eligibility for review with eligible articles read in full. The final selection of reviews was critically appraised using the ROBIS tool and pre-defined data were extracted; the primary data of interest were the anticholinergic burden scales or tools used. Results: Five reviews were identified for analysis containing a total of 62 original articles. Eighteen anticholinergic burden scales or tools were identified with variation in their derivation, content and how they quantified the anticholinergic activity of medications. The Drug Burden Index was the most commonly used scale or tool in community and database studies, while the Anticholinergic Risk Scale was used more frequently in care homes and hospital settings. The association between anticholinergic burden and clinical outcomes varied by index and study. Falls and hospitalisation were consistently found to be associated with anticholinergic burden. Mortality, delirium, physical function and cognition were not consistently associated. Conclusions: Anticholinergic burden scales vary in their rationale, use and association with outcomes. This review showed that the concept of anticholinergic burden has been variably defined and inconsistently described using a number of indices with different content and scoring. The association between adverse outcomes and anticholinergic burden varies between scores and has not been conclusively established

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival